The transient receptor potential of vanilloid type-1 (TRPV1) channel is a non-specific cation channel and plays a major role in nociceptive heat thermosensation and inflammatory hyperalgesia. It is abundantly expressed in unmyelinated sensory fibers of the Aδ- and C-type as well as in the spinal cord, and its activation in the peripheral afferents of dorsal root ganglia causes entry of calcium, depolarization and local release of algogenic peptides, such as calcitonin gene-related peptide and substance P, as well as activation of ascending pathways of pain transmission. The TRPV1 channel was discovered thanks to studies on the mechanism of action of the pro-nociceptive and thermal pain-mimicking actions of capsaicin, the pungent principle of Capsicum annum. Apart from being up-regulated during chronic pain conditions, TRPV1 exists in several phosphorylated/active and dephosphorylated/inactive forms, only the former of which are capable of mediating the gating of extracellular calcium into neurons through channel pores and subsequent depolarization. TRPV1 phosphorylation can be triggered by several algogenic mediators through the intermediacy mostly of protein kinases C and A, and, together with release of the channel from the tonic inhibitory action of phosphatidyl-inositol-bis phosphate, obtained through PI3 kinase or phospholipase C activation, it is the major molecular mechanism for its sensitization to the action of temperature, low pH (protons), endogenous agonists (endovanilloids) and toxins like capsaicin. Calcium entry also causes the desensitization of the channel, through the action of Ca2+-sensitive protein phosphatases such as calcineurin. Therefore, TRPV1 is made refractory by its agonists to further stimulation by noxious heat or endogenous algogenic mediators, thus leading to paradoxical anti-hyperalgesic actions, which are at the basis of the use of capsaicin-based creams against chronic pain.